Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The EVI1 gene encodes a zinc-finger, DNA-binding protein originally described as the transforming gene associated with a common ecotropic viral insertion site in myeloid leukemias. Previous studies demonstrated EVI1 expression in human leukemias in cases with 3q26 translocations, but not in normal blood or bone marrow. These studies also suggested an association between EVI1 expression and chromosome 7 deletion (del). Because of this association, we examined expression of EVI1 using RNA polymerase chain reaction (PCR) in patients with myelodysplastic syndromes (MDS) and acute leukemia with and without 3q26 translocations. EVI1 RNA was expressed in 29% of 34 (95% confidence interval, 20% to 50%) patients with the MDS subtypes refractory anemia (RA), refractory anemia with excess blasts (RAEB), or refractory anemia with excess blasts in transformation (RAEB-T). The vast majority of these cases occurred in patients with RAEB and RAEB-T. EVI1 expression was not detected in patients with chronic myelomonocytic leukemia (CMML), normal bone marrow or cord blood, or a variety of other hematologic malignancies. EVI1 RNA was detected in three of 18 patients with acute myelogenous leukemia (AML) and in two of four patients with acute promyelocytic leukemia (APL). Karyotypes showed that only one AML patient had karyotype 3q26 abnormalities, indicating that EVI1 expression is associated with cases that do not have structural abnormalities involving chromosome 3q26. These studies document for the first time the abnormal expression of EVI1 RNA by patients with MDS, and suggest an important role for EVI1 in the pathogenesis or progression of some myeloid malignancies.
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PMID:Expression of EVI1 in myelodysplastic syndromes and other hematologic malignancies without 3q26 translocations. 804 40

A 78 year old female was found to have pancytopenia in February 1991. Bone marrow was normocellular with 11.7% blasts and showed dysmegakaryopoietic changes. A diagnosis of MDS (RAEB) was made and she was treated with transfusions and ubenimex. Leukemic transformation was noted in July. On Admission in October 1991, her laboratory examinations revealed the following: WBC 38,900/microliters with 93% blast, Hb 8.0 g/dl, Plt 2.1 x 10(4)/microliters, a hypercellular bone marrow with 74% blasts which were negative for myeloperoxidase (MPO) by light microscopy, but were positive by electron microscopy. Surface marker for CD13 was positive. These findings corresponded to M0 of the FAB subtype. Chromosome analysis revealed Ph1 chromosome with 46XX, t (9;22) (q34;q11) in 3 of 3 cells examined, Southern analysis showed the rearrangement of the break point cluster region (bcr). Reverse transcriptase polymerase chain reaction technique demonstrated the presence of major bcr/abl mRNA. She was treated with transfusions and methyl-prednisolone. Her blast counts declined and Ph1 chromosome was only positive in 1 of 12 metaphases examined. She died of pneumonia in December 1991. Eleven cases with MDS showing Ph1 chromosome have previously been reported. The observations indicate that Ph1 chromosome positive acute leukemias were heterogenous in nature.
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PMID:[RAEB transformed into AML (M0) showing Ph1 chromosome and rearrangement of major cluster region]. 825 8

The term myelodysplasia (MDS) refers to a group of bone marrow failure syndromes which are relatively rare in childhood. The pathogenesis of MDS is unknown, but a variety of chromosomal, molecular, and cytochemical abnormalities have been reported. We describe a 4-month-old female with MDS who presented with severe neutropenia and refractory anemia with excess blasts (RAEB). Bone marrow progenitor cell assays showed decreased erythroid and myeloid colony formation as compared to normal marrow, and the patient's serum further diminished colony formation of both her own and control marrow. These observations suggested the presence of a soluble factor inhibitory to hematopoiesis. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of total RNA derived from the patient's bone marrow mononuclear cells revealed highly elevated tumor necrosis factor-alpha (TNF-alpha) mRNA levels. Using a similar RT-PCR profile, TNF-alpha mRNA levels were found to be elevated in two other children with myelodysplasia. We conclude that TNF-alpha is produced in large amounts by bone marrow mononuclear cells of children with MDS, and we hypothesize that TNF-alpha plays an important role in the pathophysiology of the ineffective hematopoiesis observed in MDS.
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PMID:Tumor necrosis factor-alpha suppresses hematopoiesis in children with myelodysplasia. 895 Mar 41

Trisomy 11 as a sole chromosomal abnormality is a rare aberration observed in myelodysplastic syndrome (MDS) or acute myeloblastic leukemia (AML). Recently a partial tandem duplication of the MLL gene, located on chromosome band 11q23, has been identified in de novo AML with trisomy 11. We describe a 72-year-old woman suffering from MDS-derived overt leukemia with trisomy 11 and a tandem duplication of the MLL gene. At first the patient was found to have myeloblasts with Auer rods in the peripheral blood and diagnosed as MDS, refractory anemia with excess of blasts in transformation (RAEB-T). After 2 months a picture of overt leukemia (AML; M2) developed as shown by an increased number of myeloblasts. Various chemotherapy regimens had little effect, and she died of disease progression 15 months after admission. During her clinical course, the chromosome analyses consistently showed 47,XX, +11. Southern blot analysis of leukemic blasts on admission and in accelerated phase revealed identical rearranged bands of the MLL gene. Fluorescence in situ hybridization analysis excluded the possibility of masked translocation of the MLL gene to other chromosomes. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis using a forward exon 6 primer and a backward exon 3 primer demonstrated an in-frame fusion of exon 8 with exon 2. Our results indicated that a partial tandem duplication of exons 2-8 of the MLL gene could be observed in MDS-derived overt leukemia as well as de novo AML with trisomy 11.
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PMID:Tandem duplication of the MLL gene in myelodysplastic syndrome-derived overt leukemia with trisomy 11. 913 17

The two matrix metalloproteinases (MMPs) Mr 72,000 type IV collagenase (MMP-2, gelatinase A) and Mr 92,000 type IV collagenase (MMP-9, gelatinase B) play key roles in tissue remodeling and tumor invasion by digestion of extracellular matrix barriers. We have investigated the production of these two enzymes as well as the membrane-type MMP (MT1-MMP) and the tissue inhibitors of metalloproteinases (TIMPs) TIMP-1 and TIMP-2 in the bone marrow mononuclear cells (BM-MNCs) of patients with acute myeloid leukemia (AML; n = 24), chronic myeloid leukemia (CML; n = 17), myelodysplastic syndromes (MDS; n = 8), and healthy donors (n = 5). Zymographic analysis of BM-MNC-conditioned medium showed that a Mr 92,000 gelatinolytic activity, identified as MMP-9 by Western blotting, was constitutively released from cells of all patients and healthy individuals examined in this study. In contrast, MMP-2 secretion was found to be absent in all samples from healthy donors but present in 8 of 11 (73%) of the samples from patients with primary AML, 7 of 8 (88%) with secondary AML, and only 1 of 5 (20%) cases with AML in remission, indicating MMP-2 to be produced by the leukemic blasts. MMP-2 release was not detected in CML cell-conditioned medium with the exception of two cases, both patients either being in or preceding blast crisis. In MDS, MMP-2 was found in three of eight (38%) of the patients, two of them undergoing progression of disease within 12 months. Quantitative Northern blot analysis in freshly isolated BM-MNCs showed a relatively low constitutive expression of TIMP-1 in all samples, whereas MMP-9 gene transcription was higher in healthy donors and CML samples, than in AML and MDS. Reverse transcriptase-PCR analysis revealed the presence of TIMP-2 mRNA in the majority of MMP-2-releasing BM-MNCs. MT1-MMP expression was present in most samples of patients with MDS or AML but absent in those with secondary AML and CML. Thus, we have shown that BM-MNCs continuously produce MMP-9 and TIMP-1 and demonstrated that leukemic blast cells additionally secrete MMP-2 representing a potential marker for dissemination in myeloproliferative malignancies.
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PMID:Matrix metalloproteinase production by bone marrow mononuclear cells from normal individuals and patients with acute and chronic myeloid leukemia or myelodysplastic syndromes. 1035 46

Thrombopoietin (TPO), a major cytokine involved in megakaryocytopoiesis/thrombopoiesis, may be effective for treatment of the thrombocytopenia associated with myelodysplastic syndromes (MDS). However, it has been unclear whether TPO stimulates proliferation of MDS blasts, as observed in de novo acute myeloid leukemia. This study examined this concern. When marrow cells from 37 MDS cases were cultured with or without recombinant human PEGylated TPO, TPO increased the blast number (stimulation index > or =1.5) in 9 of 16 high-risk MDS cases (refractory anemia with excess blasts [RAEB] and RAEB in transformation) and 4 of 10 cases with MDS transformed to acute leukemia (MDS-AL), but none of 11 cases with low-risk MDS (RA and RA with ringed sideroblasts). When the cell cycle of cultured cells was determined by three-color flow cytometry, TPO activated the cell cycle of MDS cells (causing a decrease in G(0)-phase cells) in most of the cases whose blast number increased in response to TPO. Reverse transcriptase-polymerase chain reaction analysis detected TPO receptor messenger RNA in purified blasts from all six cases examined, irrespective of the response of their blasts to TPO in culture. Analysis of the patients' characteristics identified a high-serum lactate dehydrogenase (LDH) value as being associated with blast proliferation in high-risk MDS cases (p = 0.0036). We conclude that TPO stimulates in vitro proliferation of blasts from a fraction of MDS patients. High-risk MDS patients, especially those who have a high-serum LDH value, and MDS-AL patients should be monitored with particular care in clinical trials of TPO for MDS.
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PMID:Effect of thrombopoietin on proliferation of blasts from patients with myelodysplastic syndromes. 1074 83

Gene CBP codes for a transcriptional coactivator, which can interact with many transcriptional factors. It modifies the process of transcription stimulated by these factors by specific binding to RNA polymerase II holoenzyme or by histone acetylation. CBP gene mutation is the molecular cause of autosomal dominant genetic disease called Rubinstein-Taybi syndrome that is manifested by mental and growth retardations, by typical face malformations and broad thumbs and broad big toes. The CBP gene can be affected by the t(8;16)(p11;p13.3) translocation resulting in production of the MOZ/CBP chimeric protein and in induction of acute myeloblastic leukaemia. Therapy using topoisomerase II inhibitors can induce the t(11;16)(q23;13.3) translocation causing acute myeloid or lymphoid leukaemia or myelodysplasia through production of the MLL/CBP protein chimera.
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PMID:[Clinical sequelae of mutation of the CBP gene]. 1074 38

We report a 50-year-old man who developed therapy-related myelodysplastic syndrome after treatment with etoposide-including chemotherapy for extratesticular germ cell tumor. Chromosomal analysis showed inversion 11 (p15q22) translocation. Reverse transcriptase-polymerase chain reaction amplification of patient RNA showed a fusion transcript of nucleoporin gene NUP98, and putative DEAD-box RNA helicase gene DDX10. NUP98 is implicated in the transformation through aberrant nucleocytoplasmic transport. DDX10 is suggested to be involved in ribosome assembly. The NUP98-DDX10 fusion transcript may promote the development of secondary hematological malignancies caused by DNA-topoisomerase II inhibitors through aberrant nucleocytoplasmic transport and/or alteration in ribosome assembly.
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PMID:Fusion of the nucleoporin gene, NUP98, and the putative RNA helicase gene, DDX10, by inversion 11 (p15q22) chromosome translocation in a patient with etoposide-related myelodysplastic syndrome. 2575 91

The bone marrow (BM) in myelodysplastic syndromes (MDS) undergoes pathobiological changes that mimic an inflammatory process, and hence, an infectious etiology was suspected in these disorders. In the present report, we examined the bone marrow mononuclear cells (BMMNC) of 19 MDS patients and seven normal donors for the expression of one latency-related (Latency membrane protein 1 (LMP-1) and immediate early protein (IEP)) and one activation-related (BZLF and DNA-Pol) m-RNA each for two herpes viruses, Epstein-Barr virus (EBV) and cytomegalovirus (CMV), respectively. Reverse transcriptase polymerase chain reaction was used for this purpose. The latency-related transcripts (EBV-LMP-1 and CMV-IEP) were present in all the MDS and normal specimens. Intriguingly, 10/19 MDS specimens ( approximately 53%) and 2/7 normal donors ( approximately 28%) were positive for active EBV-BZLF (P=0.0067), while 2/19 MDS specimens ( approximately 11%) with 1/7 normal ( approximately 14%) showed active CMV-DNA-Pol (P=0.1588). Later, from another set of MDS patients (n=7) and normal donors (n=4), BM stromal cultures were established, which, at a 75% confluency, were overlaid with cord blood mononuclear cells (CBMNC). IEP was detectable in the CBMNC before and after co-incubation with MDS, as well as normal stroma. So, it was also present both in MDS and normal stromal cells. The other three were absent both in MDS and normal stromal layers. In CBMNC though, active EBV-BZLF and CMV-DNA-Pol m-RNA were detectable in one of seven MDS co-cultures each, albeit from different patients. None of the normal co-cultures showed active virus, either in stroma or CBMNC. Thus, the present report demonstrates, for the first time, the presence of active herpes viruses in the BMMNC of MDS patients and reveals the ability of the MDS stroma to support the viral activation.
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PMID:Presence of activation-related m-RNA for EBV and CMV in the bone marrow of patients with myelodysplastic syndromes. 1117 35

The t(11;20)(p15;q11) is a rare but recurrent translocation that so far has been described in only four acute myeloid leukemias (AMLs), two treatment-related myelodysplastic syndromes (t-MDSs), and one case of polycythemia vera. Recently, the t(11;20) was shown to result in a fusion of the NUP98 and TOP1 genes, with expression of the NUP98/TOP1 chimera encoded by the der(11)t(11;20), but not of the reciprocal TOP1/NUP98 on the der(20)t(11;20). The genomic breakpoints were subsequently mapped to introns 13 and 7 of NUP98 and TOP1, respectively. We present here a t-MDS with a three-way variant translocation, t(10;20;11)(q24;q11;p15), that generates a der(11)t(11;20) but not a der(20)t(11;20), strongly suggesting that the der(11) harbors the critical genetic rearrangement. Reverse transcriptase-polymerase chain reaction (RT-PCR) revealed a NUP98/TOP1 fusion in which exon 13 of NUP98 was fused in-frame with exon 8 of TOP1. Extra long (XL) genomic PCR and subsequent sequence analyses showed that the breakpoint in NUP98 occurred at nucleotide (nt) 3461 of intron 13, close to a MER (medium reiteration frequency interspersed repetitive element) repeat, and that the breakpoint in TOP1 was at nt 1436 of intron 7, downstream of a MIR (mammalian-wide interspersed repeats) repetitive element. Genomic XL PCR did not amplify the reciprocal TOP1/NUP98, nor was this chimera expressed, as expected from the cytogenetic finding. The present results provide further support for the involvement of the NUP98/TOP1 transcript, but not of the reciprocal one, in the development of MDS/AML. Furthermore, the three cases genomically characterized to date have all been treatment-related and have all harbored breakpoints in intron 13 of NUP98 and intron 7 of TOP1, suggesting that these introns are susceptible to chemotherapy-induced breakage.
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PMID:Expression of NUP98/TOP1, but not of TOP1/NUP98, in a treatment-related myelodysplastic syndrome with t(10;20;11)(q24;q11;p15). 1197 59


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